The invention relates to a membrane with a double-layer membrane wall whose layers consist of different polymers or, respectively, polymer mixtures and whose one surface is blood compatible whereas the other surface is tissue compatible, a method for the manufacture of this membrane and the use of this membrane as a support membrane for bio-hybrid organs.
It is already known to use membranes for the detoxification of blood outside the body during organ failure, for example during kidney failure. In this treatment, which is used today in hospitals worldwide, toxins permeate in accordance with the pore size of the dialysis membrane used and the size of the molecules of the compounds to be removed from the blood of the patient into a flushing solution, the dialysate. This process is called herein a “passive” transport which, in accordance with the laws of diffusion, is based on the difference of the concentration of the respective compounds contained in the two liquids.
In the natural kidneys, the urine toxins are in a first stage also removed by a passive process in which the primary urine is produced. However, in contrast to the artificial kidney, this passive ultra filtration process is followed by a subsequent active process, in which certain compounds of the primary urine and particularly water are returned to the blood against the concentration gradient of the primary urine. Such an active process can be established within the artificial kidney at the present state of the membrane separation technology only by vital and tissue-like organized cell layers. The same is true for other organs, for example, the pancreas and the lever. By means of porous membranes consequently only the passive filtration functions and possibly and sorptive functions of the organs responsible for detoxification can be supported or, respectively, replaced and therefore utilized for therapeutic purposes.
There were attempts to introduce the active transport of vital cells specifically for support in dysfunctions of ailing organs. The results achieved however can hardly be used for many reasons.
In view of the clinical relevance, there were also many attempts to develop suitable membrane carriers with a property profile as required for the specific application. In principle, the membrane carriers known so far can be classified in four different basic types which differ particularly in the membrane and swelling properties:
1. Highly swelling gel membranes with membrane functions (for example, ASA10 J. 39 (1993), M261-M267; Biomaterials 16 (1995) 753-759) and, respectively, porous membranes filled with gel (for example, WO 97/17129).
2. Practically not or only moderately swelling porous membranes with membrane functions in non-functionalized form (WO 95/21911, WO 96/40871, U.S. Pat. No. 5,837,234) or functionalized form (U.S. Pat. No. 5,720,969), wherein the biochemical behavior with regard to blood and tissue compatibility may be optimized with a polymer composition of the membrane former in accordance with the requirements (see DE 100 30 307.2).
3. 3D-matrix materials without separation functions (GB 2 187 447), WO 97/12960) with extremely coarse porous structure (10-100 μm).
4. Carrier materials which were manufactured by microelectronic techniques such as thin film deposition, photolithography and/or etching (for example, U.S. Pat. Nos. 5,651,900; 5,798,042; 5,893,974; 5,938,923; 5,948,255; 5,985,328).
All these developments have in common that the requirement profile of a carrier membrane for use in bio-hybrid organs is only partially fulfilled; gel membranes or gel-filled membranes have an insufficient adherence to the adhesion-dependent cells and, up to date, provide for insufficient material exchange. Non-swelling or moderately swelling membranes do not have optimal properties with regard to blood or tissue compatibility. Even an optimized polymer composition achieves only a compromise between the two characteristics. The membrane formation in accordance with a phase inversion process is often insufficient. 3D matrix materials basically do not have an immune-isolating effect which requires the use of patient cells which are not available. The permeation properties of materials manufactured by means of microelectronic techniques are insufficient and the manufacture of relatively large membrane areas is prohibitively expensive.
It is therefore the object of the present invention to provide a carrier membrane, which can be used in bio-hybrid reactors and which can be manufactured at relatively low costs.